This disclosure is generally directed to a composition and a method for the prophylactic treatment of ketosis and related calving disorders in calving cows.
When lactation starts in dairy cows, the onset of milk production is sudden, and the nutritional requirements of the lactating cow become very high. Lactogenesis increases the demand for glucose as a precursor for lactose synthesis. Unlike monogastric mammals, ruminants—such as dairy cows—rely heavily on gluconeogenesis in the liver to meet their glucose requirements, because less glucose is absorbed in the lower digestive tract. Thus, during lactation, increased supply and digestion of carbohydrates in the rumen is necessary to meet the energy requirements of the cow. As parturition approaches, the blood sugar level of cows continues to decrease and, after parturition, it further decreases sharply.
Substantial metabolic adjustment is required to provide substrates for milk synthesis after calving. Energy deficit in early lactation is prevalent. Feed intake is depressed around calving and thus the amount of available propionate, the major glucogenic precursor formed in the rumen, is usually insufficient. When the energy requirement of the cow exceeds its energy intake, the metabolism of the cow adjusts to meet the deficit from body reserves, such as fatty tissues. Long-chain fatty acids (or non-esterified fatty acids, NEFAs) are mobilized from body fat. NEFAs, already elevated from around seven days prepartum, are a significant source of energy to the cow during the early postpartum period, and the greater the energy deficit the higher the concentration of NEFA in the blood. The circulating NEFAs are taken up by the liver and are oxidized to carbon dioxide or ketone bodies (e.g. 3-hydroxybutyrate, acetoacetic acid, and acetone), or are reconverted by esterification into triglycerides and stored. Meanwhile, the capacity of the liver for synthesizing very low density lipoproteins to export triglycerides from the liver is limited.
When the amount of ketone bodies formed exceeds the amount of ketone bodies metabolized by the cow, the ketone bodies accumulate in the blood and in the urine, which are conditions respectively known as ketonemia and ketonuria. These conditions fall under the broader classification of ketosis. Dairy cows suffering from ketosis exhibit symptoms such as poor appetite, decreased body weight, and lower milk production. Because acetoacetic acid and 3-hydroxybutyric acid are strong acids, excessive concentrations of these ketone bodies in the blood can exceed the buffering capacity of the cow's body, which in turn lowers the pH of the blood and can lead to a fatal state called ketoacidosis. Because ruminants produce butyric acid as a fermentation product in the digestive tract, which is a precursor to 3-hydroxybutyric acid, the concentration of ketone bodies in the blood even at a physiological state is higher than in non-ruminants and, therefore, the incidence of ketosis in ruminants is high.
Ketosis may be treated by intravenous administration of a solution of a sugar, such as glucose, xylitol, or the like, but the effect on reduction of the concentration of ketone bodies is transitory and lasts only a short period of time. Although continuous intravenous injection over an extended time period would address this problem in theory, such a solution is not practical in dairy farming. Another option is to repeat such single administrations frequently, which, again, is not very practical.
Other treatment options include injections of hormones or steroids, administration of glucose precursors such as propylene glycol and sodium propionate, and supplementation of other nutrients known to increase blood sugar and thus reduce ketones and fat mobilization.
For prevention of ketosis of cows, studies have indicated several strategies, including pre-fresh nutritional management combined with preventing obesity in dry cows, maximizing energy intake in early lactation, avoid feeding large quantities of poor quality grass silage high in butyric acid during the ketosis susceptible period, and supplementing the diet with glucose precursors such as propylene glycol and sodium propionate.
Some studies have evaluated the effect of various forms of methionine in the treatment or prevention of ketosis in dairy cows. Shaw, J. C., “Studies on Ketosis in Dairy Cattle. VII. The Efficacy of B Vitamins and Methionine in the Treatment of Ketosis,” J. Dairy Sci., 29:131 (1946) reports the unsuccessful treatment of two ketotic cows using daily injections or oral administration of 12.5 g of DL-methionine. McCarty et al., “Bovine Ketosis and Depressed Fat Test in Milk: A Problem of Methionine Metabolism and Serum Lipoprotein Aberration,” J. Dairy Sci., 51:459-462 (1968) reports that the oral administration of the methionine hydroxy analog (MHA) (DL-α-hydroxy-γ-methylmercaptobutyrate calcium) aided in alleviating symptoms of bovine ketosis. Waterman et al., “Methionine Hydroxy Analog Treatment of Bovine Ketosis: Effects on Circulating Metabolites and Interrelationships,” J. Dairy Sci., 55:1513-1516 (1972) reports on a trial where six cases of clinical ketosis were treated with MHA orally in 40 g doses once daily for seven days. The data demonstrated that serum ketone levels fell slowly over a 21-day examination period, but never returned to normal levels. Waterman concludes that because spontaneous recovery from ketosis is an accepted phenomenon, and in view of other studies, treating ketosis with MHA was of questionable benefit.
Griel et al., “Milk Production Response to Feeding Methionine Hydroxy Analog to Lactating Dairy Cows,” J. Dairy Sci., 51:1866-1868 (1968) evaluated the effectiveness of MHA in preventing ketosis. In that trial, MHA was supplemented into the feed as a top dressing in an amount to supply 40 g and 80 g daily to two respective test groups of cows. A third group of cows, the control group, were not fed any MHA. Feeding of the MHA began three weeks preparturition and continued for eight weeks thereafter. Because none of the animals, including those in the control group, showed clinical signs of ketosis during the trial, the results were inconclusive.
Example 2 of U.S. Pat. No. 5,741,506 to Bauchart et al. evaluated the extent to which rumen protected methionine could limit ketosis in fatty cows receiving rations with low energy concentrations. At three to four weeks preparturition, the cows were fed 40 g/day protected methionine (about 28 g digestible methionine) in a bucket with 200 g of untanned cake for five days. Then, at the third or fifth day following parturition, the same feeding was done daily up to the sixth week of lactation. The data, as summarized in Table 8, demonstrates a reduction of ketone bodies in the serum at week 2 of lactation, which then significantly increased at week four of lactation.